Malignant melanoma occurs mainly in cutaneous form but is very rarely seen in mucosal form. Mucosal melanoma of the head and neck composes 0.7% to 0.8% of total malignant melanomas and 8% of total malignant melanomas of the head and neck^1,2. The median age of such patients is 70 years, and the incidence rate is twice that of Caucasians_’ than that of Americans_’ ³. The lesion is very invasive, with a 5-year survival rate of 25% to 34% with a poorer prognosis than mucosal or vulvar form^4-7.

Treatment type and prognosis are unclear due to the rarity of the tumor and its short survival period⁸. However, for resectable tumors, the most common treatment is complete surgical resection^{9 -11}. Adjuvant radiotherapy is recommended to prevent local recurrence^9,12, but the exact regimen of survival benefits of definitive/adjuvant systemic therapy are not currently reported¹³.

Since malignant mucosal melanoma of the head and neck was first reported by Lincoln in 1885, approximately 1,000 cases have been published¹⁴. This report compares the treatment received by 20 patients diagnosed with malignant mucosal melanoma in the head and neck and evaluates the effectiveness of immunotherapy.

This study was approved by the Institutional Review Board of Yonsei University Dental Hospital (IRB No. 2-2019-0075) and the written informed consent was waived by the IRB.

Among the 25 patients diagnosed with malignant mucosal melanoma who visited Yonsei University Dental Hospital from January 2008 to December 2018, the medical records of 20 were reviewed; the other 5 patients had undergone surgery and observation at other clinics or departments.

The patients’ clinical information of treatment, adjuvant chemotherapy, survival or most recent observation time, presence or absence of recurrence or metastasis, and age at death was obtained retrospectively based on written and electronic medical records.

In the 20 patients who were suspected of cancer and visited the clinic, incisional biopsy was performed. Computed tomography and positron emission tomography imaging was conducted on patients confirmed with mucosal malignant melanoma to examine the scope of surgery and metastasis. All biopsies were reviewed and diagnosed by one or more oral pathologists.

Survival analysis was completed with using the Kaplan–Meier method, while survival curve comparisons were performed using the log-rank test. The categorical variables were compared using the chi-square test, with statistical significance assigned at P<0.05. Statistical processing of the data was performed with IBM SPSS Statistics (ver. 25.0; IBM, Armonk, NY, USA).

Malignant mucosal melanoma is a rare disease, with a prevalence less than 1% of all melanomas including cutaneous forms and of less than 10% of all melanomas of the head and neck. Although staging of mucosal melanoma is challenging due to the lack of clear parameters affecting the survival rate, existing TNM staging based on the size of the tumor, was reported to be significant in predictions of overall survival and progress-free survival compared to staging based on degree of local recurrence, distant metastasis, or depth of invasion in cases of sinonasal melanoma. The older was the person, the higher was the prevalence rate, with most patients in their 70s, a similar age at diagnosis to that of cutaneous melanoma¹⁵. Most of the epidemiological and clinical data in this study were comparable to those reported in the literature. Twenty patients with malignant mucosal melanoma of the head and neck were analyzed. The average age of the patients was 55.9 years, and the oldest was 72 years, with an average observation period of 44.3 months (range, 1-152 months), which is not significantly different from that of other published studies. The prevalence of men was higher in our clinic compared to studies that reported women to have more common outbreaks than men^16,17 and reports that there was no difference in prevalence between men and women¹⁵.

Although no principles of proper management or prognosis have been established due to the rarity of the tumor and its short survival rate⁸, radiotherapy is strongly recommended for patients with resectable tumors within 6 weeks after complete resection⁹. However, there are no reports on a clear survival benefit of systemic therapy^1,9-¹³. In our clinic, surgical resection was prioritized in patients (n=17, 85.0%) with resectable primary lesions without distant metastasis. Patients with positive surgical margin or with local recurrence underwent radiotherapy. Systemic therapy was performed regardless of the surgical margin if node metastases or adjacent invasion was present. The mean survival is 49.8 months when accompanied by surgical treatment, but it decreased to 12.3 months when radiotherapy or systemic therapy including immunotherapy was performed without surgical treatment, which is the same trend as large-sample reports stating that survival is longer when surgical resection is performed¹⁸.

Due to the difficulty in assessing the efficacy of systemic therapy and the limitation of excluding distant metastasis in most phase II clinical trials, there is no established regimen for primary lesions¹³. In our cases, patients received a dacarbazine single regimen and an anti PD-1 agent (pembrolizumab) as adjuvant systemic therapy and an anti CTLA-4 agent (ipilimumab) with an anti PD-1 agent (pembrolizumab) for advanced and recurrent lesions. Large-scale random trials of anti CTLA-4 and anti PD-1 for malignant mucosal melanoma of the head and neck have yet to be carried out¹⁹, while there are several smaller clinical trials reporting on malignant mucosal melanoma of the entire body, including overall survival and disease-free survival rates. It was possible to compare our hospital’s treatment compared to 11.3 months and 12.1 months of survival periods and 2.8 months of disease free survival on average of few small keynote studies of 8 to 16 people whom being treated with immunotherapy exclusively^20-22.

In our hospital, the average observation period for the group of patients (n=12) who did not undergo immunotherapy was 34.2 months (range, 1-104 months), and the average disease-free survival was 31.3 months (range, 1-104 months). For patients who underwent immunotherapy as a secondary treatment after conventional therapy other than immunotherapy, the average observation period was 93 months, with a disease-free survival of 76 months. For patients who received immunotherapy as the primary treatment (n=4), the average observation period was 19.3 months, and the disease free survival was 16.3 months. As seen in the survival curve of Fig. 4, use of immunotherapy as a secondary treatment exhibited a higher tendency for survival compared to using only systematic regimens other than immunotherapy, but the difference was not statistically significant.

This report is not a random trial for a particular treatment, but a retrospective study of a previously conducted treatment. In addition, this report had statistical limitations in analyzing treatment methods and their regimens due to small sample sizes. In our clinic, surgical resection is the first choice in operable patients, and adjuvant therapy is administered based on the margin status and permanent pathologic diagnosis. In the case of systemic therapy, for which guidelines remain unclear, immunotherapy was performed when local recurrence or disease progression was diagnosed. In our clinic, overall survival was longer when radiotherapy or immunotherapy was combined with surgery and was longer than in previous reports. This tendency has been improved through development of treatments and immunotherapy²³. This implies further improvement of treatment methods based on future developments.